Laboratory of B cell Immunoregulation

The Laboratory of B cell Immunoregulation is led by Laurent Verkoczy, PhD. The overall focus of the laboratory of B cell immunoregulation is to identify viral and host determinants involved in controlling B cell responses required for generating “broadly neutralizing” antibodies (bnAbs) to the HIV-1 gp41 Membrane Proximal External Region (MPER).

A major goal of the Verkoczy lab is to use normal, autoimmune, and gene-targeted mouse models to identify the spectrum of B cells interacting with gp41 MPER epitopes (or autoantigens cross-reacting with the MPER) and to determine the immunoregulatory mechanisms controlling MPER bnAb-specific B cell responses. In an important set of “proof of concept” studies towards this goal, the Verkoczy lab has generated an array of knock-in mice expressing different portions of the original MPER-specific bnAbs 2F5 and 4E10. They are currently using these mice to directly examine the role of B cell tolerance (central and peripheral) in regulating MPER bnAb-specific B cells and to determine the B cell subsets affected and the mechanisms involved. In another set of studies, Dr. Verkoczy and his colleagues have used IgH congenic mouse strains to identify and map unusual, non-clonal allotypic interactions of IgMa-bearing naïve B cell populations with gp41 MPER residues lying outside the 2F5 core neutralization motif. Using a combination of approaches, they are currently investigating the hypothesis that these allotypic interactions underlie a novel immunoregulatory mechanism involving “superantigen-like” activity of the MPER that may divert or delete desired antigen-reactive B cells.

As part of the Haynes Vaccine Discovery Consortia (VDC) within the Collaboration for AIDS Vaccine Discovery (CAVD), another goal of the Verkoczy lab is to determine how the interplay between MPER immunogen/adjuvant formulations and B cell immunoregulatory/genetic controls impact MPER B cell responses. To do this, they will use 2F5 and 4E10 knock-in mice, either alone, or crossed to mouse strains defective in B cell tolerance checkpoints, as models for testing the ability of existing and novel MPER immunogens (identified by the Alam and Chen/Harrison groups) to shape the MPER bnAb-specific B cell repertoire and to gain insight into how affinity maturation impacts this process. Additionally, the Verkoczy lab will follow up on earlier observations by testing if MPER immunogens lacking “superantigen-binding” residues can “focus” bnAb MPER-specific Ab responses and identifying the underlying factors controlling the strain-specific differences in anti-MPER antibody responses.